Glidants and process for preparing the same

ABSTRACT

Improved glidants having excellent gliding properties, i.e., improving or eliminating those disadvantages encountered in the prior art, for example, capping of the finished pharmaceutical preparations, delayed disintegration of the finished pharmaceutical preparations, lowering of the dissolution-out rate of the active ingredient and the like, which comprises certain known glidants wet-treated with a surface active agent, said known glidants being selected from higher fatty acids, the metal salts thereof and hydrogenated vegetable oils. The present glidants are prepared by subjecting the known glidants to wet treatment with a surface active agent.

United States Patent Nakajima et al.

GLIDANTS AND PROCESS FOR PREPARING THE SAME Inventors; Eiichi Nakajima;Tadashi Morioka;

K020 Kurihara; Takashi Kobayashi, all of Tokyo, Japan Assignee: SankyoCompany Limited, Tokyo,

Japan Filed: July 29, 1974 Appl. No.: 492,786

Related US. Application Data Continuation of Ser. No. 336,372, Feb, 27,1973, abandoned.

Foreign Application Priority Data Mar. 27, 1970 Japan 45-25756 US. Cl.252/11; 252/33; 252/39; 252/52 A; 252/56 R; 252/565; 424/14; 424/22;424/44 1m. C1 ClOM 1/40; ClOM 3/34; ClOM 5/16; ClOM 7/22 Field of Search424/14, 22, 44; 252/11, 252/39, 33,56 R, 56 s, 52

[56] References Cited UNITED STATES PATENTS 3,5 l8.345 6/1970 Dines etal 252/11 3,518,346 6/l970 Cox 252/ll 3,719,599 3/1973 Gianbattista etal 252/11 Primary ExaminerDelbert E. Gantz Assistant E.\'aminerl. VaughnAttorney, Agent, or FirmFlynn & Frishauf 57 ABSTRACT Improved glidantshaving excellent gliding properties, i.e., improving or eliminatingthose disadvantages encountered in the prior art, for example, cappingof the finished pharmaceutical preparations, delayed disintegration ofthe finished pharmaceutical preparations, lowering of thedissolution-out rate of the active ingredient and the like, whichcomprises certain known glidants wet-treated with a surface activeagent, said known glidants being selected from higher fatty acids, themetal salts thereof and hydrogenated vegetable oils. The presentglidants are prepared by subjecting the known glidants to wet treatmentwith a surface active agent.

9 Claims, No Drawings GLIDANTS AND PROCESS FOR PREPARING THE SAME Thisis a continuation of application Ser. No. 336,372, filed Feb. 27, 1973,and now abandoned.

This invention relates to improved glidants and a process for preparingthe same.

More particularly, it is concerned With improved glidants comprising aglidant substance wherein said glidant substance is subjected to wettreatment with a surface active agent, said glidant substance beingselected from the group consisting of higher fatty acids. the metalsalts thereof and hydrogenated vegetable oils and with a process for thepreparation of such improved glidant.

It is wellknown in the art that a certain type of adjuvants or glidantswhich have been widely employed for the production of variouspharmaceutical preparations, e.g.. powders, capsules, tablets and thelike have troublesome disadvantages that they show such undesirablecharacteristics as poor disintegration of the finished pharmaceuticalpreparation, prolonged dissolutionout rate of the active ingredient,especially they have a pronounced tendency to cause capping when used inmaking tablets. In some cases, other types of glidants such as boricacid, sodium benzoate, sodium chloride, leucine. Carbowax (RegisteredTrade Mark), sodium stearate and the like have been also utilized in thepharmaceutical preparations, especially those required for hydrophilicproperty, e.g., water-soluble tablets, but these glidant substances wereknown to exert a poor glidant effect as well as toxicity andhygroscopicity so that they were kept away from general utilizability.

As a result of our extensive studies to develop a new and improvedglidant having no disadvantages as seen in the prior art glidants, ithas been unexpectedly found that a certain type of the known glidantsubstances, i.e., those selected from the group consisting of higherfatty acids, the metal salts thereof and hydrogenated vegetable oilsexhibit a highly excellent glidant effect when they are subjected to wettreatment with a surface active agent.

The above finding is quite surprising because it has been generallyunderstood in the art that a glidant exhibits its glidant effect due toits surface properties and thus, when treated with a substance having nogliding property per se, such a glidant should lose its inherent glidantproperty.

However, in contrary to the above-depicted prejudice, the improvedglidant of this invention can hold inherent glidant effects such as theimprovement in fluidity, the lowering of the excluding force frompunches upon making tablets, the increase in bulk density, theprevention of anchoring and the like and simultaneously perform almostcomplete elimination of the disadvantages accompanied with the prior artglidants. e.g., poor disintegration, lower dissolution-out rate and thelike, as compared with the prior art glidants. Still more surprisingly,in the case of making tablets the improved glidant of this invention caneffectively prevent the low tablet hardness and the development ofcapping, which are believed inherent in the prior art glidant.

It is, therefore, a primary object of this invention to provide animproved glidant which shows highly excellent glidant ability withoutthe disadvantages inherent in the prior art, expecially capping, delayeddisintegration and low dissolution-out rate. 1

It is another object of this invention to provide a process 'forthepreparation of an improved glidant having desirable characteristics.

These objects and the advantages of this invention will be apparent tothose skilled in the art from the detailed description below.

The glidant of this invention, as explained above. has an essentialfeature that it comprises a glidant substance known per se, saidsubstance being selected from the group consisting of higher fattyacids, the metal salts thereof and hydrogenated vegetable oils, whichsubstance is subjected to wet treatment (or treat ment under a wettingcondition) with a surface active agent. I

The term wet treatment" as used herein is contemplated to includekneading procedure and other procedures commonly employed for absorptionbetween solid phase and liquid phase.

In another aspect of this invention, the process of this inventioncomprises subjecting the selected glidant substance to wet treatmentwith a surface active agent.

In effecting the process of this invention, the preferred embodiment canbe carried out according to the flow sheet as illustrated below.

. Drying Surface I Solvent Dissolution o Glidant of Lhisl invention Inthe abovementioned embodiment, the wet treatment may be effected as setforth above. The drying may be suitably effected by a conventionaldrying procedure, e.g. hot air drying, aeration drying, vacuum dryingand the like. The pulverization may be suitably effected by means of aconventional grinder, e.g.. impact grinder, pneumatic grinder and thelike. It is desirable that the particle size of the ground glidant be inthe range of 10 ,u or less, but larger particle size may also befavourably employed. Examples of the glidant substances to be treatedaccording to the process of this invention include stearic acid,magnesium stearate, calcium stearate and hydrogenated castor oil [e.g.Lubriwax (trade name, available from F reund Industrial Company, Japan)and Sterotex (trade name, available from Capital City Products Company,U.S.A)]. If desired, any combination of the above-illustrated glidantsubstances may also be employed in this invention. The surface activeagents which may be employed in this invention may be of any type ofnon-ionic, anionic and cationic type surface active agents. Of thesesurface active agents are preferable polyoxyethylenepolyoxypropyleneblock polymers, e.g., those having the structure Hon? H OJ1(C;,H.,O)b(C-H O)CH wherein either the sum ofa and c is 30 35 and b is 25 30 or thesum ofa and cis -150 and b is 25 30 and a molecularweight of either ca.3000 or ca. 8,000. respectively [e.g. Pluronic F-68" and Pluronic L'64(trade names. available from Asahi Denka Kogyo K.K.. Japan or fromWyandotte Chemical Co.. USA. )1. polyoxyethylene sorbitan fatty acidesters. e.g.. polyoxyethylene monostearate. monolaurate. monopalmitate.monooleate and trioleate; alkyl sulfate salts. e.g.. sodium laurylsulfate: and the like. The amount of the surface active agent to beemployed is not critical. but it is usual and effective to employ thesurfactant at 20 7c by weight or less. preferably at 4 '7( by weight.based upon the total weight of the untreated glidant substance. Thesolvent which may be employed in the above wet treatment may be any ofthose that could dissolve the surfactant and not the untreated glidantsubstance. Examples of the solvents which may be employed include water.methanol. ethanol. acetone. chloroform and the like.

The following Examples are given for the purpose of illustrating of theadvantages and embodiments of this invention. but they should not beconstrued to be limiting the scope of this invention. All parts andpercentages are given by weight.

Table l Surface active agent Solvent Ptnl ox eth lene sorhitan A(Ethanol) monolaurate Polyoxyeth lene sorbitan B (Ethanol) tristearateSorhitan monolaurate C (Ethanol) Sorhitan monooleate D (Ethanol)Pluronic L-fi4 E (Water) Pluronic F-os F (Water) Sodium lauryl sulfate G(Water) *Extruding force from the cylinder upon the pressure-moldedproduct (Kg/cm) *Angle of repose of the powder llowctl out of thefunnel.

EXAMPLE 1 The surface active agents indicated in the Table I below wererespectively dissolved in the solvents indicated in the Table I to formthe 5 7c solutions thereof.

It will be seen from the above Table II that the glidants of thisinvention exhibit excellent properties.

EXAMPLE 2 The molded products from the formulations indicated in thefollowing Table [II and the No. 1 capsules filled with the sameformulations were tested for their physical properties as below with theresults which are summarized in the Table IV below.

Table III Sample No.

Chloramphenicol parts) I00 I00 I00 I00 100 I00 Lactose (parts) 40 39.?39.3 39.3 37.2 37.2 37.2 Untreated StMg (parts) 0.7 2 .66 Sodium laurylsulfate (powder. less than l(),u. parts) 0.7 0.]4 StMg treated withsodium lauryl sulfate (less than 0.7 2.8

l() u. parts) Total (parts) l40 I40 l40 I40 l-10 I40 [00 parts of StMgas subjected to wet treatment with an 5; aqueous solution ofsodium laur\l sulfate. dried and then pul\ erized.

Table IV Compound No. l 2 3 4 5 (1 7 Specific extruding force (kg/cm)L50 1.05 0.48 0449 0.50

Table IV-continued Compound No. l 2 3 4 5 o 7 Disintegration time ofcapsulelmin) X 8 I I 8 8 25 IS It will be seen from the above Table IVthat the incor- Table VII poration of the surfactant alone does notprovide so much appreciable glidant effect (Sample No. 2). the Sump H HH incorporation of the StMg alone provides a good glidant effect butpoor disintegration ability (Sample Nos. Lactose gmnules (PMS) 3 I d 6 dth f l Untreated StMglparts) In an an e incorporation o asimp e mixtureof StMg treated with sodium the surfactant and the StMg gives aninsufficient period lauryl u (P l of disintegration time (Sample No. 7),whereas the Tom] (pans, 3015 glidants treated with the surfactantsolution according x I r v g to this invention exert the desired effect(Sample Nos. The Mme m the 4 and 5 EXAMPLE 3 Five hundred mg. of thegranule sample as obtained The powdery formulations shown in thefollowing above was molded under pressure of 1 ton by means of Table Vwere formed by utilizing the treated StMg a conventional compressiontester equipped with flat prepared in the above Example I and filledinto No. 0 punches of l 1 mm. diameter. whereupon the excludingcapsules. which were then subjected to a dissolutionforce from the punchwas determined with a load cell. out test. The results are summarized inthe following Table The results are summarized in the Table VI below.VIII.

Table V Sample No.

9 It) 11 I2 Chloramphenicol (parts) 500 SUI) 500 500 500 Lactose (parts)I50 I20 I 20 I20 I20 Untreated StMg (partsl 3U (B)* (parts) 30 (F)*(parts) 3U (6)" (parts) 30 Total (parts) 650 650 650 650 650 The same asin the ahou: Table I.

Table VI Table VIII l Excluding force Amount of the active ingredienteluted ('7?) 40 Sample No {mm [hc punch g Dissolution-out time l0 min.20 min. 30 min Sample No. 15 92 a 81 95 98 9 5 14 23 ll) I5 76 5 II It)45 78 It Wlll be seen from the above Table ,VIII that the 3 99formulation containing the StMg treated with the surfactant (Sample No.14) has a reducing action against the force excluding the tablets fromthe punch. i.e.. a glidant action as the formulation containing the un-It will be seen from the above Table VI that. when treated StMg (SampleNo. 13) has.

I u f he lidan is formulated, the such a arge amo nt 0 t g t EXAMPLE 5formulation contalning the conventional or untreated StMg (Sample No. 9)shows much lower dissolution- The powdery formulations were preparedhaving the out rate as compared with that containing no glidant formulasas indicated in the following Table IX. (Sample No. 8), whereas theformulations containing Table IX the StMg treated according to thisinvention (Sample Nos. 10. l l and I2) undergo little influence withsuch Sample l 6 17 lg factors and show a good dissolution-out rate.

Ground sugar (parts) I070 I058 U158 Methyl cellulose (50 opts ll) l0 l0parts) EXAMPLE 4 Talc (parts) I20 1:11

L'ntreated Luhriwax (parts) l2 An appropriate amount of lactose wasgranulated Luhriwax treated with sorhitan monolaurate" 12 with a 4 7cstarch paste and then dried. To the so obtained granules wasincorporated the glidant indicated (,5 T l (puns) I2 I2 0 in thefollowing Table VII. The resulting granules were molded and tested asfollows.

50 parts of an lll'll elhnnulic solution of sorhitzin mnnnluurute wasmixed and kneaded with low parts of Luhriuax. dried in vacuum and thenpuherired.

One thousand and two hundred mg. of the sample as obtained above wasmolded under pressure of 3.3 tons by means of a conventional compressiontester equipped with flat punches of 16 mm. diameter. whereupon theexcluding force from the punch was determined with a load cell.

Table X Sample No. Excluding force from the punch lkg.)

It will be seen from the above Table X that the formulation containingthe Lubriwax treated with sorbitan monolaurate (Sample No. 18) exhibitsa superior glidant power to that of the formulation containing theuntreated Lubriwax (Sample No. l7).

EXAMPLE 6 The granules were prepared by incorporating a 4 starch pasteto an appropriate amount of lactose and then granulating. The so otainedgranules were punched to the tablets having an uniform tablet heightaccording to the formulae indicated in the Table Xl below.

*The same as in the above Example 2. Prepared b the same procedure asthat of the just abme l.

The test results of the tablets thus prepared are summarized in thefollowing Table Xll.

7 Table xn Sample No.

Strength of tablet (kg.) 3.2 5.5 5.2 Capping number* 12/20 0/20, 0/20Disintegration time (min.) l l 14 *WehstenAhhe abrasion tester. in 2minutes.

It will be seen from the above Table XlI that the tablets containing theglidants treated with a surfactant (Sample Nos. 20 and 21 have nocapping. a high strength and a satisfactory disintegration time.

What is claimed is:

1. A glidant comprising a major amount of a glidant substance selectedfrom the group consisting of a higher fatty acid. a calcium saltthereof, a magnesium salt thereof. and a solid hydrogenated vegetableoil. treated with a solvent solution containing a surface active agentin an amount sufficient to improve dissolution of the glidant substance.said solvent being a solvent for said surface activeagent and anon-solvent for said glidant substance. followed by drying and pulveri-Zation.

2. The glidant according to claim 1 wherein said glidant substance isstearic acid, magnesium stearate. calcium stearate or hydrogenatedcastor oil.

3. The glidant according to claim 1 wherein said surface active agent isa non-ionic. anionic or cationic surface active agent.

4. The glidant according to claim 1 wherein said surface active agent isa polyoxyethylene-polyoxypropylene block polymer. a polyoxyethylenesorbitan fatty acid ester or an alkyl sulfate salt.

5. The glidant according to claim 1 wherein said surface active agent isa polyoxyethylene-polyoxypropylene block polymer having the structurewherein either the sum of a and c is 30 35 35 and b is 25 30 or the sumofa and c is and b is 25 30 and having a molecular weight of eitherabout 3,000 or about 8.000; a polyoxyethylene sorbitan monoor tri-fattyacid ester having 12 18 carbon atoms in the fatty acid moiety; or sodiumlauryl sulfate.

6. The glidant according to claim 1 wherein said surface active agent isemployed in an amount of up to 20% by weight, based upon the totalweight of said glidant substance.

7. The glidant according to claim 1 wherein said glidant substance ismagnesium stearate and said surface active agent is sodium laurylsulfate.

8. The glidant according to claim 1 wherein said glidant substance ismagnesium stearate and said surface active agent is apolyoxyethylene-polyoxypropylene block polymer having the structureHO(C- -H O)a(CxH.;O)h(C H O)cH wherein either the sum ofa and c is 30 35and b is 25 30 or the sum ofa and c is 140 150 and b is 25 30 and havinga molecular weight of either about 3.000 or about 8.000.

9. The glidant according to claim 1 wherein the solvent is watermethanol. ethanol. acetone or chloro-

1. A GLIDANT COMPRISING A MAJOR AMOUNT OF A GLIDANT SUBSTANCE SELECTEDFROM THE GROUP CONSISTING OF A HIGHER FATTY ACID, A CALCIUM SALTTHEREOF, A MAGNESIUM SALT THEREOF, AND A SOLID HYDROGENATED BEGETABLEOIL, TREATED WITH A SOLVENT SOLUTION CONTAINING A SURFACE ACTIVE AGENTIN AN AMOUNT SUFFICIENT TO IMPROVE DISSOLUTION OF THE GLIDANT SUBSTANCE,SAID SOLVENT BEING A SOLVENT FOR SAID SURFACE ACTIVE AGENT AND ANON-SOLVENT FOR SAID GLIDANT SUBSTANCE, FOLLOWED BY DRYING ANDPULVERIZATION.
 2. The glidant according to claim 1 wherein sAid glidantsubstance is stearic acid, magnesium stearate, calcium stearate orhydrogenated castor oil.
 3. The glidant according to claim 1 whereinsaid surface active agent is a non-ionic, anionic or cationic surfaceactive agent.
 4. The glidant according to claim 1 wherein said surfaceactive agent is a polyoxyethylene-polyoxypropylene block polymer, apolyoxyethylene sorbitan fatty acid ester or an alkyl sulfate salt. 5.The glidant according to claim 1 wherein said surface active agent is apolyoxyethylene-polyoxypropylene block polymer having the structureHO(C2H4O)a(C3H6O)b(C2H4O)cH wherein either the sum of a and c is 30 - 3535 and b is 25 -30 or the sum of a and c is 140 - 150 and b is 25 - 30and having a molecular weight of either about 3,000 or about 8,000; apolyoxyethylene sorbitan mono- or tri-fatty acid ester having 12 - 18carbon atoms in the fatty acid moiety; or sodium lauryl sulfate.
 6. Theglidant according to claim 1 wherein said surface active agent isemployed in an amount of up to 20% by weight, based upon the totalweight of said glidant substance.
 7. The glidant according to claim 1wherein said glidant substance is magnesium stearate and said surfaceactive agent is sodium lauryl sulfate.
 8. The glidant according to claim1 wherein said glidant substance is magnesium stearate and said surfaceactive agent is a polyoxyethylene-polyoxypropylene block polymer havingthe structure HO(C2H4O)a(C3H6O)b(C2H4O)cH wherein either the sum of aand c is 30 - 35 and b is 25 - 30 or the sum of a and c is 140 - 150 andb is 25 - 30 and having a molecular weight of either about 3,000 orabout 8,000.
 9. The glidant according to claim 1 wherein the solvent iswater methanol, ethanol, acetone or chloroform.